| 1. |
- Benkwitz-Bedford, Sam, et al.
(författare)
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Machine Learning Prediction of Resistance to Subinhibitory Antimicrobial Concentrations from Escherichia coli Genomes.
- 2021
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Ingår i: mSystems. - 2379-5077. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- Escherichia coli is an important cause of bacterial infections worldwide, with multidrug-resistant strains incurring substantial costs on human lives. Besides therapeutic concentrations of antimicrobials in health care settings, the presence of subinhibitory antimicrobial residues in the environment and in clinics selects for antimicrobial resistance (AMR), but the underlying genetic repertoire is less well understood. Here, we used machine learning to predict the population doubling time and cell growth yield of 1,407 genetically diverse E. coli strains expanding under exposure to three subinhibitory concentrations of six classes of antimicrobials from single-nucleotide genetic variants, accessory gene variation, and the presence of known AMR genes. We predicted cell growth yields in the held-out test data with an average correlation (Spearman's ρ) of 0.63 (0.36 to 0.81 across concentrations) and cell doubling times with an average correlation of 0.59 (0.32 to 0.92 across concentrations), with moderate increases in sample size unlikely to improve predictions further. This finding points to the remaining missing heritability of growth under antimicrobial exposure being explained by effects that are too rare or weak to be captured unless sample size is dramatically increased, or by effects other than those conferred by the presence of individual single-nucleotide polymorphisms (SNPs) and genes. Predictions based on whole-genome information were generally superior to those based only on known AMR genes and were accurate for AMR resistance at therapeutic concentrations. We pinpointed genes and SNPs determining the predicted growth and thereby recapitulated many known AMR determinants. Finally, we estimated the effect sizes of resistance genes across the entire collection of strains, disclosing the growth effects for known resistance genes in each individual strain. Our results underscore the potential of predictive modeling of growth patterns from genomic data under subinhibitory concentrations of antimicrobials, although the remaining missing heritability poses a challenge for achieving the accuracy and precision required for clinical use. IMPORTANCE Predicting bacterial growth from genome sequences is important for a rapid characterization of strains in clinical diagnostics and to disclose candidate novel targets for anti-infective drugs. Previous studies have dissected the relationship between bacterial growth and genotype in mutant libraries for laboratory strains, yet no study so far has examined the predictive power of genome sequence in natural strains. In this study, we used a high-throughput phenotypic assay to measure the growth of a systematic collection of natural Escherichia coli strains and then employed machine learning models to predict bacterial growth from genomic data under nontherapeutic subinhibitory concentrations of antimicrobials that are common in nonclinical settings. We found a moderate to strong correlation between predicted and actual values for the different collected data sets. Moreover, we observed that the known resistance genes are still effective at sublethal concentrations, pointing to clinical implications of these concentrations.
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| 2. |
- Bergström, Anders, et al.
(författare)
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A high-definition view of functional genetic variation from natural yeast genomes.
- 2014
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 1537-1719 .- 0737-4038. ; 31:4, s. 872-88
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Tidskriftsartikel (refereegranskat)abstract
- The question of how genetic variation in a population influences phenotypic variation and evolution is of major importance in modern biology. Yet much is still unknown about the relative functional importance of different forms of genome variation and how they are shaped by evolutionary processes. Here we address these questions by population level sequencing of 42 strains from the budding yeast Saccharomyces cerevisiae and its closest relative S. paradoxus. We find that genome content variation, in the form of presence or absence as well as copy number of genetic material, is higher within S. cerevisiae than within S. paradoxus, despite genetic distances as measured in single-nucleotide polymorphisms being vastly smaller within the former species. This genome content variation, as well as loss-of-function variation in the form of premature stop codons and frameshifting indels, is heavily enriched in the subtelomeres, strongly reinforcing the relevance of these regions to functional evolution. Genes affected by these likely functional forms of variation are enriched for functions mediating interaction with the external environment (sugar transport and metabolism, flocculation, metal transport, and metabolism). Our results and analyses provide a comprehensive view of genomic diversity in budding yeast and expose surprising and pronounced differences between the variation within S. cerevisiae and that within S. paradoxus. We also believe that the sequence data and de novo assemblies will constitute a useful resource for further evolutionary and population genomics studies.
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| 3. |
- Bushell, Ellen, et al.
(författare)
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Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes
- 2017
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Ingår i: Cell. - : Cell Press. - 0092-8674 .- 1097-4172. ; 170:2, s. 260-272.e1-e4
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Tidskriftsartikel (refereegranskat)abstract
- The genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2,578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage of its complex life cycle, P. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probable consequence of functional optimization necessitated by genomic reductions during the evolution of parasitism. In contrast, extreme functional redundancy has evolved among expanded gene families operating at the parasite-host interface. The level of genetic redundancy in a single-celled organism may thus reflect the degree of environmental variation it experiences. In the case of Plasmodium parasites, this helps rationalize both the relative successes of drugs and the greater difficulty of making an effective vaccine.
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| 4. |
- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 5. |
- Cubillos, Francisco A, et al.
(författare)
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Assessing the complex architecture of polygenic traits in diverged yeast populations.
- 2011
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Ingår i: Molecular ecology. - 1365-294X. ; 20:7, s. 1401-13
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Tidskriftsartikel (refereegranskat)abstract
- Phenotypic variation arising from populations adapting to different niches has a complex underlying genetic architecture. A major challenge in modern biology is to identify the causative variants driving phenotypic variation. Recently, the baker's yeast, Saccharomyces cerevisiae has emerged as a powerful model for dissecting complex traits. However, past studies using a laboratory strain were unable to reveal the complete architecture of polygenic traits. Here, we present a linkage study using 576 recombinant strains obtained from crosses of isolates representative of the major lineages. The meiotic recombinational landscape appears largely conserved between populations; however, strain-specific hotspots were also detected. Quantitative measurements of growth in 23 distinct ecologically relevant environments show that our recombinant population recapitulates most of the standing phenotypic variation described in the species. Linkage analysis detected an average of 6.3 distinct QTLs for each condition tested in all crosses, explaining on average 39% of the phenotypic variation. The QTLs detected are not constrained to a small number of loci, and the majority are specific to a single cross-combination and to a specific environment. Moreover, crosses between strains of similar phenotypes generate greater variation in the offspring, suggesting the presence of many antagonistic alleles and epistatic interactions. We found that subtelomeric regions play a key role in defining individual quantitative variation, emphasizing the importance of the adaptive nature of these regions in natural populations. This set of recombinant strains is a powerful tool for investigating the complex architecture of polygenic traits.
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| 6. |
- Cubillos, Francisco A, et al.
(författare)
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High-resolution mapping of complex traits with a four-parent advanced intercross yeast population.
- 2013
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Ingår i: Genetics. - : Oxford University Press (OUP). - 1943-2631. ; 195:3, s. 1141-55
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Tidskriftsartikel (refereegranskat)abstract
- A large fraction of human complex trait heritability is due to a high number of variants with small marginal effects and their interactions with genotype and environment. Such alleles are more easily studied in model organisms, where environment, genetic makeup, and allele frequencies can be controlled. Here, we examine the effect of natural genetic variation on heritable traits in a very large pool of baker's yeast from a multiparent 12th generation intercross. We selected four representative founder strains to produce the Saccharomyces Genome Resequencing Project (SGRP)-4X mapping population and sequenced 192 segregants to generate an accurate genetic map. Using these individuals, we mapped 25 loci linked to growth traits under heat stress, arsenite, and paraquat, the majority of which were best explained by a diverging phenotype caused by a single allele in one condition. By sequencing pooled DNA from millions of segregants grown under heat stress, we further identified 34 and 39 regions selected in haploid and diploid pools, respectively, with most of the selection against a single allele. While the most parsimonious model for the majority of loci mapped using either approach was the effect of an allele private to one founder, we could validate examples of pleiotropic effects and complex allelic series at a locus. SGRP-4X is a deeply characterized resource that provides a framework for powerful and high-resolution genetic analysis of yeast phenotypes and serves as a test bed for testing avenues to attack human complex traits.
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| 7. |
- Glass, Daniel, et al.
(författare)
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Gene expression changes with age in skin, adipose tissue, blood and brain.
- 2013
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 14:7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age.RESULTS: Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues.CONCLUSIONS: Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.
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| 8. |
- Grundberg, Elin, et al.
(författare)
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Mapping cis- and trans-regulatory effects across multiple tissues in twins.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.
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| 9. |
- Ibstedt, Sebastian, 1983, et al.
(författare)
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Dissection of advanced intercross lines provides information on evolution of yeast in shifting metal abundances
- 2012
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Ingår i: Experimental Approaches to Evolution and Ecology using Yeast (EMBO, Heidelberg, October 2012). ; 2012
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Metals can be friends or foes, depending on their chemical reactivity, dose or mode of exposure. Unfortunately, a general perspective on the importance of different processes for maintaining evolutionary flexibility and physiological homeostasis with regard to metal exposure is lacking. In order to understand the processes that contribute to metal toxicity and resistance in natural populations of Saccharomyces cerevisiae, we have analyzed a twelfth generation intercross between geographically and ecologically distinct populations. Large-scale phenotyping of highly recombined segregants allows us to pinpoint causative alleles to narrow intervals and to make inferences about the evolutionary history of complex traits in natural populations with regard to pleiotropy and epistasis. We show that metal detoxification in Saccharomyces cerevisiae is highly dependent on specific stress, while epistasis depends on population-specific alleles. These results are consistent with an evolutionary history of bottle-necks, rapid dispersion into ecologically differing habitats followed by independent evolutionary paths.
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| 10. |
- Liti, Gianni, et al.
(författare)
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Population genomics of domestic and wild yeasts.
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 458:7236, s. 337-41
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Tidskriftsartikel (refereegranskat)abstract
- Since the completion of the genome sequence of Saccharomyces cerevisiae in 1996 (refs 1, 2), there has been a large increase in complete genome sequences, accompanied by great advances in our understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions, population structure and sexual versus asexual reproduction. Less well understood at the whole genome level are the evolutionary processes acting within populations and species that lead to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to fourfold or more coverage of the genome sequences of over seventy isolates of the baker's yeast S. cerevisiae and its closest relative, Saccharomyces paradoxus. We examine variation in gene content, single nucleotide polymorphisms, nucleotide insertions and deletions, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. S. paradoxus populations are well delineated along geographic boundaries, whereas the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.
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